Process for the preparation of a PDE4 inhibitor

ABSTRACT

The present invention relates to a process for the preparation of compounds endowed with phosphodiesterase (PDE4) inhibitory activity having formula (I). The invention also relates to the process for the isolation by crystallization of the compound (I) and to its use for the preparation of pharmaceutical compositions for inhalation in combination with suitable carriers or vehicles. The present invention also relates to solvates and crystal forms of a compound of formula (I). The synthesized product is suitable for use in pharmaceutical applications for instance in the treatment of respiratory diseases.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to European Patent Application No.13189784.5 filed on Oct. 22, 2013, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to processes for the preparation ofcompounds endowed with phosphodiesterase (PDE4) inhibitory activity. Thepresent invention also relates to processes for the isolation bycrystallization of such a compound and to its use for the preparation ofpharmaceutical compositions for inhalation in combination with suitablecarriers or vehicles. The present invention also relates to solvates andcrystal forms of such a compound. The synthesized product is suitablefor use in pharmaceutical applications for instance in the treatment ofrespiratory diseases.

Discussion of the Background

Compounds of formula (I) wherein n is 0 or 1:

with chemical names(S)-3-Cyclopropylmethoxy-4-methanesulfonylamino-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester and (S)-3-Cyclopropylmethoxy-4-methanesulfonylamino-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethylester, obtained according to the invention, may be used for prophylacticpurposes or for symptomatic relief for a wide range of conditionsincluding respiratory disorders such as chronic bronchitis, chronicobstructive pulmonary disease (COPD), asthma of all types and allergicdisease states such as atopic dermatitis and allergic rhinitis. Saidcompounds are disclosed in WO 2010/089107, which is incorporated hereinby reference in it is entirety, as potent PDE4 inhibitors havingexcellent LPDE4 selectivity.

Processes for the preparation of compounds of formula (I) wherein n is 0or 1 and analogues thereof, were also disclosed in WO 2010/089107, whichis incorporated herein by reference in it is entirety.

Thus, there remains a need for improved processes for the preparation ofsuch compounds.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelprocesses for the preparation of compounds of formula (I).

This and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discovery ofprocesses for the preparation of compounds of formula (I).

In particular, the present invention provides processes for thepreparation of the compounds of formula (I) wherein n is 0 or 1 and thechiral carbon atom marked with an asterisk in the formula below has the(S) configuration.

Said compounds are therapeutically useful because of their action asPDE4 inhibitors, so that related pharmaceutical compositions comprisingthem may be used in the prevention and treatment of respiratory diseasessuch as COPD (chronic bronchitis and emphysema), asthma, allergicrhinitis and atopic dermatitis; allergic disease states, inflammatoryarthritis; Crohn's disease; reperfusion injury of the myocardium andbrain; cystic fibrosis, arterial restenosis, atherosclerosis, keratosis,rheumatoid spondylitis, osteoarthritis, pyresis, diabetes mellitus,pneumoconiosis, toxic and allergic contact eczema; systemic lupuscrythematosus, follicular and wide-area pyodermias, endogenous andexogenous acne, acne rosacea, Beghet's disease, anaphylactoid purpuranephritis, inflammatory bowel disease, leukemia, multiple sclerosis,gastrointestinal diseases, autoimmune disease; neurological andpsychiatric disorders; stroke and spinal cord injury.

The invention relates to a particularly efficient process for thepreparation of the compounds of formula (I) alternative to the onedisclosed in the above cited prior art document.

This method is particularly advantageous in comparison with the knownone because it provides for a simpler and safer procedure, with improvedcontrol of the process parameters and reproducibility, reduced number ofsynthesis steps and intermediate isolation, higher atom efficiency,reduced amounts of solvents, higher yields of products formation, andreduced impurities.

This method is also particularly suitable for industrial scalemanufacturing.

A thermodynamically stable crystal form of the compound of formula (I)wherein n is 1, which will be hereinafter referred to as Form A,characterized by a high level of chemical purity and crystallinity aswell as good handling qualities for pharmaceutical use, may be obtainedaccording to the process of the present invention.

Crystal Form A of the present invention, for which its characteristicpeaks in the X-ray powder diffraction (XRPD) pattern and melting rangeare given, may be selectively produced through crystallization by usingappropriate solvents and operative conditions, as per the followingdetailed section.

Accordingly, the present invention also provides processes for thepreparation of said Crystal Form A, comprising crystallization orre-crystallization under selected conditions.

As the said Crystal Form A may be used for prophylactic or therapeuticpurposes, the present invention further provides the use of Crystal FormA of the compound of formula (I) wherein n is 1 in the manufacture of amedicament for the prevention and/or treatment of an inflammatory orobstructive respiratory disease such as asthma or chronic obstructivepulmonary disease (COPD).

In a still further aspect, the present invention provides a method ofpreventing and/or treating an inflammatory or obstructive respiratorydisease such as asthma or chronic obstructive pulmonary disease (COPD),which comprises the inhalatory administration of an effective amount ofcrystal Form A.

Solvates of the compound of formula (I) wherein n is 1 are also obtainedby operating with appropriate solvents.

Accordingly, the present invention also provides processes for thepreparation of said solvates.

In particular, a solvate of a compound of formula (I) is obtained fromethanol and is distinguishable based upon its characteristic peaks inthe X-ray powder diffraction (XRPD) pattern, and its characteristicmelting range.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the present invention and many of theattendant advantages thereof will be readily obtained as the same becomebetter understood by reference to the following detailed descriptionwhen considered in connection with the accompanying drawings, wherein:

FIG. 1 is the differential scanning calorimetry (DSC) thermal trace ofsolvate from ethanol of the compound of formula (I) wherein n is 1.

FIG. 2 is the Raman spectrum of solvate from ethanol of the compound offormula (I) wherein n is 1.

FIG. 3 is the XRPD pattern of solvate from ethanol of the compound offormula (I) wherein n is 1.

FIG. 4 is the differential scanning calorimetry (DSC) thermal trace ofthe Crystalline Form A from ethyl acetate/n-heptane.

FIG. 5 is the Raman spectrum of the Crystalline Form A from ethylacetate/n-heptane.

FIG. 6 is the XRPD pattern of the Crystalline Form A from ethylacetate/n-heptane, recorded on a Bruker D8 Advance with Xray DiffractionTube type KFL Cu 2k.

FIG. 7 is the XRPD pattern of the Crystalline Form A from isopropylacetate.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as it is commonly understood by one of ordinaryskill in the art to which this subject matter belongs.

The term “high level of chemical purity” refers to a crystal formwherein the total amount of readily detectable impurities as determinedby standard methods of analysis, such as thin layer chromatography (TLC)or high performance liquid chromatography (HPLC) is less than 5%,advantageously less than 2.5%, even less than 1.0%, or more preferablyeven less than 0.5% w/w.

The term “high level of crystallinity” refers to a crystal form whereinthe percentage of crystallinity is equal to or higher than 90%,preferably higher than 95% w/w as determined by standard methods ofanalysis, such as X-ray powder diffraction or microcalorimetry.

The present invention provides a process for preparing a compound offormula (I):

wherein n is 0 or 1, which process comprises:

(a) reacting a compound of formula (II):

wherein n is 0 or 1, with a compound of formula (III):

wherein X is selected from —NHSO₂Me and —NO₂ and Z is selected from —OH,chlorine, bromine, linear or branched (C₁-C₆)alkoxy, aryloxy,arylalkoxy, (C₁-C₆)alkylcarbonyloxy, arylcarbonyloxy, andaryl(C₁-C₆)alkylcarbonyloxy to obtain a compound of formula (I) whereinn is 0 or 1 or a compound of formula (IV):

wherein n has the above reported meanings; and, when a compound offormula (IV) is obtained in step (a):

(b) reducing it to a corresponding compound of formula (V):

wherein n is 0 or 1, and reacting it with methanesulfonyl halide toobtain a compound of formula (I) wherein n has the above reportedmeanings;

and wherein the compound of formula (II) in step (a) is obtainedaccording to any one of the alternative steps (c1) or (c2) or (c3) by:

(c1) oxidizing a compound of formula (VI):

wherein n is 0 or 1 to obtain a compound of formula (VII):

wherein n is 0 or 1, and subsequently enantioselectively reducing it toobtain a compound of formula (II) wherein n has the above reportedmeanings; or

(c2) chromatographically separating a compound of formula (VI) wherein nis 0 or 1, to obtain both a compound of formula (II) and a compound offormula (VIII):

wherein n has the above reported meanings;

and optionally oxidizing the compound of formula (VIII) obtained in step(c2) to a corresponding compound of formula (VII) to be subsequentlyreduced to a compound of formula (VI) wherein n is 0 or 1 andreprocessed in the following chromatographic separation process; or

(c3) reacting an intermediate of formula B″:

with an intermediate of formula D:

wherein R is a linear or branched (C₁-C₆) alkyl group or a arylalkylgroup and n has the above reported meanings, to obtain directly acompound of formula (VII) and subsequently enantioselectively reducingit to obtain a compound of formula (II) wherein n has the above reportedmeanings;

and wherein all of the compounds of formula (I), (II), (IV), (V), (VI),(VII), or (VIII) wherein n is 1 can be obtained by oxidizing thecorresponding compounds wherein n is 0.

In the present description, and unless otherwise provided, the bond withthe symbol:

-   -           in formula (VI) indicates a racemic mixture of the two        enantiomers (R) and (S).

The bond with the symbol:

-   -           in formulae (I) and (II) indicates the enantiomer (S), whereas        the bond with the symbol:    -           in formula (VIII) indicates the enantiomer (R).

The term linear or branched (C₁-C₆) alkyl group stands for a linear orbranched alkyl group with from 1 to 6 carbon atoms, for example methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, n-hexyl, and the like.

The term (C₁-C₆)arylalkyl refers to (C₁-C₆)alkyl groups furthersubstituted by aryl.

The term linear or branched (C₁-C₆) alkoxy group means any alkyl-oxychain wherein alkyl stands for a linear or branched alkyl group withfrom 1 to 6 carbon atoms, for example methoxy, ethoxy, n-propyloxy,isopropyloxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy,n-hexyloxy, and the like, preferably methoxy.

The term aryloxy group means any aryl group linked to the rest of themolecule through an oxygen atom, i.e. aryl-O— group. To this extent, andunless otherwise provided, aryl stands for an aromatic carbocyclic ringor aromatic heterocyclic ring, for instance comprising 5 or 6 memberedrings with from 1 to 3 heteroatoms or heteroatomic groups selected fromN, NH, O or S. The phenoxy group is preferred.

The term arylalkoxy means any (C₁-C₆)alkoxy substituted by one or morearyl groups, as defined above. Benzyloxy is preferred.

The term arylalkylcarbonyloxy means any (C₁-C₆)alkylcarbonyloxysubstituted by one or more aryl groups, as defined above, preferablybenzylcarbonyloxy.

The term halide, when referring to methanesulfonyl halide in step (b) ofthe process of the invention, means chloride and bromide.

In a preferred embodiment, the present invention provides a process forthe preparation of a compound of formula (I) wherein n is 0 or 1, whichprocess comprises reacting, in step (a), a compound of formula (II)wherein n has the above reported meanings with a compound of formula(III) wherein X is NHSO₂Me and Z has the above reported meanings.

According to an alternative preferred embodiment, the present inventionprovides a process for the preparation of a compound of formula (I)wherein n is 0 or 1, which process comprises reacting, in step (a), acompound of formula (II) wherein n has the above reported meanings witha compound of formula (III) wherein X is —NO₂ and Z has the abovereported meanings.

According to a further preferred embodiment, the present inventionprovides a process for the preparation of a compound of formula (I)wherein n is 0 or 1, which process comprises reacting the compound offormula (II) being obtained as per step (c1), by oxidizing a compound offormula (VI) to a compound of formula (VII) and by enantioselectivelyreducing this latter to a compound of formula (II), wherein n has theabove reported meanings.

According to a further preferred embodiment, the present inventionprovides a process for the preparation of a compound of formula (I)wherein n is 0 or 1, which process comprises reacting the compound offormula (II) obtained as per step (c2), by chromatographicallyseparating a compound of formula (VI) to obtain both a compound offormula (II) and of formula (VIII), wherein n has the above reportedmeanings.

Even more preferably, according to this latter embodiment, the presentinvention provides a process for the preparation of a compound offormula (I) wherein n is 0 or 1, which process comprises reacting thecompound of formula (II) obtained as per step (c2), bychromatographically separating a compound of formula (VI) to obtain botha compound of formula (II) and of formula (VIII), wherein n has theabove reported meanings, and by then oxidizing the compound of formula(VIII) to a corresponding compound of formula (VII) to be subsequentlyreduced to a compound of formula (VI) that can be recycled in a furtherchromatographic separation.

According to a further preferred embodiment, the present inventionprovides a process for the preparation of a compound of formula (I)wherein n is 0 or 1, which process comprises reacting the compound offormula (II) obtained as per step (c3), reacting an intermediate offormula B″:

with an intermediate of formula D

to obtain directly a compound of formula (VII) and subsequentlyenantioselectively reducing it to obtain a compound of formula (II)wherein n has the above reported meanings.

According to an additional preferred embodiment, the present inventionprovides a process for the preparation of a compound of formula (I)wherein n is 1, which process comprises oxidizing a compound of formula(I) wherein n is 0.

Alternatively, the present invention provides a process for thepreparation of a compound of formula (I) wherein n is 1 by starting froma compound of formula (II) wherein n is 1, this latter having beenobtained by oxidation of the corresponding compound of formula (II)wherein n is 0.

Alternatively, the present invention provides a process for thepreparation of a compound of formula (I) wherein n is 1 by starting froma compound of formula (IV) wherein n is 1, this latter having beenobtained by oxidation of the corresponding compound of formula (IV)wherein n is 0.

Alternatively, the present invention provides a process for thepreparation of a compound of formula (I) wherein n is 1 by starting froma compound of formula (V) wherein n is 1, this latter having beenobtained by oxidation of the corresponding compound of formula (V)wherein n is 0.

Alternatively, the present invention provides a process for thepreparation of a compound of formula (I) wherein n is 1 by starting froma compound of formula (VI) wherein n is 1, this latter having beenobtained by oxidation of the corresponding compound of formula (VI)wherein n is 0.

Alternatively, the present invention provides a process for thepreparation of a compound of formula (I) wherein n is 1 by starting froma compound of formula (VII) wherein n is 1, this latter having beenobtained by oxidation of the corresponding compound of formula (VII)wherein n is 0.

According to step (a) of the present invention, the process provides forthe preparation of a compound of formula (I) or of formula (IV) byreacting a compound of formula (II) with a compound of formula (III)wherein n, X and Z have the above reported meanings.

More in particular, when the compound of formula (III) is used wherein Zis —OH, the reaction is carried out in the presence of a couplingreagent selected from DCC, CDI, HATU, HBTU, TBTU, DMTMM, COMU, EDCI,with or without HOBt, with or without an organic base like TEA, DIPEA,NMM, DBU, DBO, pyridine, and DMAP, in a solvent selected from dimethylsulfoxide, sulfolane, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidone, toluene, benzene, xylene, acetone, isopropyl ketone, methylethyl ketone, methyl isobutyl ketone, THF, dioxane, 2-methoxyethylether, diethyl ether, isopropyl ether, t-butyl methyl ether, ethylacetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform,chlorobenzene, and mixtures thereof.

When the compound of formula (III) is an acyl chloride or bromide, or anactivated ester or a mixed anhydride, the reaction is carried out asabove described without the presence of a coupling reagent.

Preferably, the above reaction with a compound of formula (III) whereinX is —NHSO₂Me is conducted with CDI and DBU in ethyl acetate.

In an alternative preferred embodiment, when the reaction is carried outwith a compound of formula (III) wherein X is —NO₂, so as to give riseto a compound of formula (IV), the above reaction is conducted with EDCIand DMAP in DMF.

According to step (b) of the process, to be optionally carried out whenstarting from a compound of formula (III) wherein X is —NO₂ in step (a),the compound of formula (IV) wherein n has the above reported meaningsis first reduced to the corresponding amino derivative of formula (V)and then properly reacted with a methanesulfonyl halide to obtain thecompound of formula (I).

Preferably, the reducing step is carried out with a reducing agentselected from hydrogen, cyclohexadiene, ammonium formate, formic acid,iron, tin dichloride, tin, nickel chloride, nickel, lithium aluminiumhydride, sodium aluminium hydride, lithium borohydride, sodiumborohydride, potassium borohydride, and sodium hydrosulfite.

In an even more preferred embodiment, when the reaction is carried outwith hydrogen, cyclohexadiene, ammonium formate and formic acid, thenthe reaction is carried out in the presence of a catalyst selected frompalladium-platinum- or nickel-based catalysts, or it is selected fromthe group consisting of palladium on carbon, palladium on bariumsulphate and palladium on calcium carbonate.

In an even more preferred embodiment, when formic acid is used, thereaction is carried out in the presence of ammonia or an amine,preferably triethylamine.

Suitable solvents for the above reducing step are selected from water,methanol, ethanol, isopropanol, n-butanol, t-butanol, dimethylformamide, dimethyl acetamide, N-methyl pyrrolidone, toluene, benzene,xylene, THF, dioxane, 2-methoxyethyl ether, diethyl ether, isopropylether, t-butyl methyl ether, ethyl acetate, isopropyl acetate,acetonitrile, and mixtures thereof.

More preferably, the reaction is carried out with hydrogen withpalladium on charcoal in ethyl acetate.

The subsequent reaction of the compound of formula (V) withmethanesulfonyl halide is carried out in the presence of suitablesolvents such as toluene, benzene, xylene, tetrahydrofuran, dioxane,2-methoxyethyl ether, diethyl ether, isopropyl ether, t-butylmethylether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane,chloroform, chlorobenzene, and mixtures thereof and a base preferablyselected from sodium hydroxide, sodium carbonate, sodium bicarbonate,sodium hydride, potassium hydroxide, potassium carbonate, potassiumbicarbonate, lithium hydroxide, lithium carbonate, caesium hydroxide,caesium carbonate, caesium bicarbonate, TEA (triethylamine), DIPEA(Hünig Base, diisopropylethyl-amine), NMM (N-Methylmorpholine), DBU(1,8-Diazabicyclo[5.4.0]undec-7-ene), DBO(1,4-Diazabicyclo[2.2.2]octane), pyridine, and DMAP(4-dimethylaminopyridine); in the case when pyridine is used in excessother solvents can be avoided.

Preferably, the reaction is carried out with triethylamine indichloromethane.

According to step (c1) for the preparation of the compound of formula(II), the compound of formula (VI) is first oxidized to thecorresponding keto derivative of formula (VII) which is thenenantioselectively reduced to the compound of formula (II).

Oxidation is preferably carried out in the presence of an oxidizingagent selected from a metallic oxide such as MnO₂, a hypervalent iodine,like 2-Iodoxybenzoic acid (IBX) or Dess-Martin periodinane,dimethylsulfoxide-based oxidants (Swern) like sulfur trioxide pyridinecomplex, in a solvent selected from water, dimethyl formamide, dimethylacetamide, N-methyl pyrrolidone, dimethyl sulfoxide, sulfolane, toluene,benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methylisobutyl ketone, ethyl acetate, isopropyl acetate, acetonitrile,dichloromethane, THF, dioxane, and mixtures thereof.

Even more preferably the reaction is carried out with MnO₂ in toluene orwith a Swern oxidant in DMSO.

Compound of formula (VI) can be prepared from intermediate of formula B:

and intermediate of formula D wherein n=0

as described in WO 2010/089107, which is incorporated herein byreference in its entirety.

According to step (c3) for the preparation of the compound of formula(II), the intermediate of formula B′:

is converted to intermediate of formula B″:

by reaction with thionyl chloride, hydrogen chloride, sulfuric acid inmethanol, ethanol, isopropanol, n-butanol, t-butanol, benzyl alcoholwith or without other solvents, or by reaction with the relative alkylhalide in the presence of suitable solvents such as methanol, ethanol,isopropanol, n-butanol, t-butanol, dimethyl formamide, dimethylacetamide, N-methyl pyrrolidone, tetrahydrofuran, dioxane, ethylacetate, isopropyl acetate, acetonitrile, dichloromethane, and mixturesthereof and a base preferably selected from sodium hydroxide, sodiumcarbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate,potassium bicarbonate, lithium hydroxide, lithium carbonate, caesiumhydroxide, caesium carbonate, caesium bicarbonate, TEA (triethylamine),DIPEA (Hünig Base, diisopropylethyl-amine), NMM (N-Methylmorpholine),pyridine.

More preferably, the above reaction is conducted with potassiumcarbonate in dimethyl formamide or dimethyl acetamide.

Intermediate B′ can be obtained by oxidation of intermediate B with anoxidizing agent selected from hydrogen peroxide, an organic peracid,like paracetic acid, or m-chloroperbenzoic acid, or a mineral peracidlike persolforic acid or Oxone® (KHSO₅*½KHSO₄*½K₂SO₄), in the presenceof suitable solvents such as water, methanol, ethanol, isopropanol,n-butanol, t-butanol, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidone, tetrahydrofuran, dioxane, 2-methoxyethyl ether, isopropylacetate, acetonitrile, and mixtures thereof. More preferably, the abovereaction is conducted with Oxone® in methanol.

Alternatively intermediate B″ can be prepared directly from intermediateB by oxidation with Oxone® in the corresponding alkyl alcohol assolvent.

Alternatively intermediate B″ can be prepared from conversion ofintermediate C′ into intermediate C″:

by Pinner reaction with sulfuric acid in the corresponding alkyl alcoholas solvent, followed by alkylation with cyclopropyl bromide in thepresence of suitable solvents such as toluene, benzene, xylene,tetrahydrofuran, dioxane, 2-methoxyethyl ether, diethyl ether, isopropylether, t-butylmethyl ether, ethyl acetate, isopropyl acetate,acetonitrile, dichloromethane, chloroform, chlorobenzene, and mixturesthereof and a base preferably selected from sodium hydroxide, sodiumcarbonate, sodium bicarbonate, sodium hydride, potassium hydroxide,potassium carbonate, potassium bicarbonate, lithium hydroxide, lithiumcarbonate, caesium hydroxide, caesium carbonate, caesium bicarbonate,TEA (triethylamine), DIPEA (Hünig Base, diisopropylethyl-amine), NMM(N-Methylmorpholine), DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene), DBO(1,4-Diazabicyclo[2.2.2]octane), pyridine, and DMAP(4-dimethylaminopyridine).

Intermediate B″ is then converted to the corresponding keto derivativeof formula (VII) by reaction with intermediate D in presence of a basepreferably selected from lithium diisopropylamide (LDA), butyl lithium,hexyl lithium, pentyl lithium, lithium bis(trimethylsilyl)amide (LHMDS),sodium bis(trimethylsilyl)amide, and potassium t-butylate, in thepresence of suitable solvents such as toluene, benzene, xylene,tetrahydrofuran, methyl-tetrahydrofuran, dioxane, 2-methoxyethyl ether,diethyl ether, isopropyl ether, t-butylmethyl ether, and mixturesthereof.

More preferably, the above reaction is conducted with LHMDS in THF.

The subsequent enantioselective reducing step is preferably carried outwith a reducing agent selected from hydrogen in the presence of a heavymetal chiral complex pre-formed or formed in situ. In situ formation mayoccur by reacting a Ru-, Rh- or Ir-complex such as RuCl₂(PPh₃)₃, [Ru(p-cymene)Cl₂]₂, [RhCI₂(Cp*)]₂ or [IrCI₂(Cp*)]₂ with a chiral ligandsuch as SL-N004-1((S)-4-tert-Butyl-2-[(S)-2-(bis(1-phenyl)phosphino)ferrocen-1-yl]oxazoline,),SL-N003-1((R)-4-Isopropyl-2-[(R)-2-(diphenylphosphino)-ferrocen-1-yl]Oxazoline),(S,S)-Ts-DPEN ((1S,2S)-(−)-N-p-tosyl-1,2-diphenylethylenediamine),(S,S)-Ms-DPEN ((1S,2S)-(−)-N-Mesyl-1,2-diphenylethylenediamine),(R)-DAIPEN((2R)-(−)-1,1-Bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine), or (1R,2S)-1-Amino-2-indanol.

The above reduction reaction is preferably carried out in the presenceof a base, preferably selected from sodium hydroxide, sodium carbonate,sodium C₁-C₄ alcoholates, sodium bicarbonate, sodium hydride, potassiumhydroxide, potassium carbonate, potassium C₁-C₄ alcoholates, potassiumbicarbonate, lithium hydroxide, lithium carbonate, lithium C₁-C₄alcoholates, caesium hydroxide, caesium carbonate, caesium bicarbonate,triethyl amine, pyridine, and 4-dimethylaminopyridine.

In an even more preferred embodiment, the reaction is carried out withthe complex formed in situ by reacting RuCl₂(PPh₃)₃ and the chiralligand SL-N004-1, in toluene and in the presence of aqueous sodiumhydroxide.

Alternatively the compounds of formula (II) and (VIII) may be separatedby preparative chiral chromatography; a batch procedure may be adoptedloading the chiral column with a solution of racemic (VI) in severalruns and collecting the eluted fractions of separated enantiomers. Asimulated moving bed (SMB) procedure should be considered to separatelarge amounts of material.

Advantageously, according to an alternative embodiment of the presentinvention, once the compounds of formula (II) and (VIII) have beenseparated through preparative chiral HPLC techniques, the compound offormula (VIII) may be conveniently reconverted into the compound offormula (VI) through oxidation to the corresponding derivative offormula (VII) and subsequent reduction and reprocessed in the followingchromatographic separation process, as formerly reported.

The reduction can be carried out with lithium aluminium hydride, sodiumaluminium hydride, lithium borohydride, sodium borohydride, or potassiumborohydride in a solvent like water, methanol, ethanol, isopropanol,n-butanol, t-butanol, toluene, benzene, xylene, THF, dioxane,2-methoxyethyl ether, diethyl ether, isopropyl ether, t-butyl methylether, and mixtures thereof.

It should be understood that all of the compounds of the presentinvention wherein n is 0 can be transformed into corresponding compoundswherein n is 1 by oxidation with an oxidizing agent selected fromhydrogen peroxide, an organic peracid, like paracetic acid, orm-chloroperbenzoic acid, or a mineral peracid like persolforic acid, orOxone® (KHSO₅*½KHSO₄*½K₂SO₄), in a solvent selected from the groupconsisting of water, methanol, ethanol, isopropanol, n-butanol,t-butanol, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone,toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethylketone, methyl isobutyl ketone, THF, dioxane, ethyl acetate, isopropylacetate, acetonitrile, acetic acid, and mixtures thereof.

More preferably, the above reaction is conducted on (I) or on (II)wherein n is 0 with Oxone® in water and methanol.

From all of the above, it is clear that when preparing the compounds offormula (I) according to any one of the aforementioned process variants,optional functional groups within the starting materials or theintermediates thereof and which could give rise to unwanted sidereactions, need to be properly protected according to conventionaltechniques. Likewise, the conversion of these latter into the freedeprotected compounds may be carried out according to known procedures.

The intermediate compounds of formula (IV) and (V) and wherein n is 0 or1 are novel and, hence, represent a further embodiment of the presentinvention.

The compounds of formula (VI), as starting materials of the presentprocess, are known or can be prepared according to known methods.

As an example, the compounds of formula (VI) and their preparation aredisclosed in WO 2010/089107, which is incorporated herein by referencein its entirety.

Compound of formula (III) wherein X is —NHSO₂Me and Z is —OH representsa further embodiment of the present invention.

The other starting materials of formula (III) are known or readilyprepared according to known methods.

As an additional example, the compounds of formula (III) wherein X is—NHSO₂Me can be prepared from the corresponding derivatives wherein X is—NO₂ by reduction of these latter to the amino derivatives and by theirsubsequent reaction with a methanesulfonyl halide, essentially asformerly described.

Likewise, the preparation of the compounds of formula (III) where Z is—OH can be obtained through conventional hydrolysis of the correspondingester derivatives.

To this extent, the hydrolysis reaction for instance occurring on acompound of formula (III) wherein Z is methoxy can be easilyaccomplished in the presence of a suitable base selected from sodiumhydroxide, sodium carbonate, potassium hydroxide, potassium carbonate,lithium hydroxide, lithium carbonate, caesium hydroxide, and caesiumcarbonate; the solvent being selected from water alone or in mixturewith methanol, ethanol, isopropanol, n-butanol, t-butanol, dimethylsulfoxide, sulfolane, toluene, benzene, xylene, THF, dioxane, andmixtures thereof.

More preferably, the hydrolysis reaction of the esters into the freeacid wherein Z is —OH is carried out with NaOH in THF and water.

Likewise, the preparation of the compounds of formula (I) wherein Z isother than —OH can be accomplished according to well-knownesterification or transesterification techniques or starting from therelative ester of the 3-hydroxy-4-nitrobenzoic acid.

The present invention also provides a process for the preparation ofadditional compounds of formula (IX) that, with respect to the abovecompounds of formula (I), bear additional R₁ and R₂ groups in place ofthe cyclopropylmethyl and difluoromethyl groups of formula (I).

Said compounds of formula (IX) may be used for prophylactic purposes orfor symptomatic relief for a wide range of conditions includingrespiratory disorders such as chronic bronchitis, chronic obstructivepulmonary disease (COPD), asthma of all types and allergic diseasestates such as atopic dermatitis and allergic rhinitis.

Accordingly, the present invention also provides a process for thepreparation of the compounds of formula (XI):

wherein n is 0 or 1;

and R₁ and R₂, are independently selected in a group consisting of H,linear or branched (C₁-C₆) alkyl, optionally substituted by one or moresubstituents selected from halogen atoms, (C₃-C₇) cycloalkyl;(C₅-C₇)cycloalkenyl; linear or branched (C₂-C₆) alkenyl;aryl(C₂-C₆)alkenyl and linear or branched (C₂-C₆) alkynyl,

which process comprises:

(a) reacting a compound of formula (X):

wherein n is 0 or 1, with a compound of formula (III):

wherein X is selected from —NHSO₂Me and —NO₂ and Z is selected from —OH,chlorine, bromine, linear or branched (C₁-C₆)alkoxy, aryloxy,arylalkoxy, (C₁-C₆)alkylcarbonyloxy, arylcarbonyloxy andaryl(C₁-C₆)alkylcarbonyloxy, to obtain a compound of formula (XI)wherein n is 0 or 1 or a compound of formula (XII):

wherein R1, R2, and n have the above reported meanings; and, when acompound of formula (XII) is obtained in step (a):

(b) reducing it to a corresponding compound of formula (XIII):

wherein R1, R2, and n have the above reported meanings, and reacting itwith methanesulfonyl halide to obtain a compound of formula (XI) whereinn has the above reported meanings;

and wherein the compound of formula (X) in step (a) is obtainedaccording to any one of the alternative steps (c1) or (c2) by:

(c1) oxidizing a compound of formula (XIV):

wherein n is 0 or 1 to obtain a compound of formula (XV):

wherein n is 0 or 1, and subsequently enantioselectively reducing it toobtain a compound of formula (X) wherein n has the above reportedmeanings; or

(c2) chromatographically separating a compound of formula (XIV) whereinn is 0 or 1, to obtain both a compound of formula (X) and a compound offormula (XVI):

wherein n has the above reported meanings;

and optionally oxidizing the compound of formula (XVI) obtained in step(c2) to a corresponding compound of formula (XV) to be subsequentlyreduced to a compound of formula (XIV) wherein n is 0 or 1 andreprocessed in the following chromatographic separation process;

and wherein all of the compounds of formula (XI), (X), (XII), (XIII),(XIV), (XV) or (XVI) wherein n is 1 can be obtained by oxidizing thecorresponding compounds wherein n is 0.

From all of the above, it is clear that the operative conditionsapplicable to the aforementioned steps of the process for thepreparation of the compounds of formula (I) may apply as well to thepreparation of the compounds of formula (XI).

The intermediates compounds of formula (XII) and (XIII) and wherein n is0 or 1 are novel and, hence, represent a further embodiment of thepresent invention.

The starting material of formula (X) is known or readily preparedaccording to known methods.

In a further even more preferred embodiment, when compound (I) wherein nis 0 or 1 is obtained, it may be purified by crystallization or crushingfrom one or more solvents preferably selected from water, methanol,ethanol, isopropanol, n-butanol, t-butanol, toluene, benzene, xylene,acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone,THF, dioxane, 2-methoxyethyl ether, diethyl ether, isopropyl ether,t-butyl methyl ether, ethyl acetate, isopropyl acetate, dichloromethane,an aliphatic or aromatic hydrocarbon, preferably chosen from the groupconsisting of pentane, hexane, heptane, cyclohexane, andmethylcyclohexane or mixture thereof.

The reaction is preferably carried out in ethyl acetate with n-heptane.

In another preferred embodiment, the present invention relates to theprocess for the isolation by crystallization of the compound (I) and toits use for the preparation of pharmaceutical compositions forinhalation in combination with suitable carriers or vehicles.

In another preferred embodiment, the present invention provides aprocess for the preparation of Crystal Form A from ethyl acetate andn-heptane, characterized by the following characteristic XRPD peaks:7.48; 7.93; 8.55; 10.15; 10.32; 12.72; 13.51; 16.18; 16.46; 17.79;18.08; 18.53; 18.94; 19.1; 19.89; 20.2; 21.37; 22.96; 23.63; 24.87;25.82; 26.51; 28.09; and 28.61±0.2 degrees/2 theta.

In another preferred embodiment, the present invention is directed tothe use of Crystal Form A for the prevention and/or treatment of aninflammatory or obstructive respiratory disease such as asthma orchronic obstructive pulmonary disease (COPD).

In a still further aspect, the present invention is directed to a methodof preventing and/or treating an inflammatory or obstructive respiratorydisease such as asthma or chronic obstructive pulmonary disease (COPD),which comprises the inhalatory administration of an effective amount ofCrystal Form A.

In another preferred embodiment, the present invention is directed to aprocess for the preparation of solvates of a compound of formula (I).

In another preferred embodiment, the invention is directed to a processfor the preparation of a solvate of a compound of formula (I) fromethanol, characterized by the following characteristic XRPD peaks: 7.45;7.87; 8.51; 10.12; 10.28; 12.66; 13.29; 13.45; 14.95; 16.14; 16.34;17.05; 17.74; 18.05; 18.48; 18.88; 19.05; 19.33; 19.85; 20.18; 20.65;21.3; 22.96; 23.55; 23.87; 24.41; 24.66; 24.88; 25.62; 25.82; 26.45;28.12; and 28.53-0.2 degrees/2 theta.

Pharmaceutical compositions can be prepared by admixture of compounds offormula (I) wherein n is 0 or 1 prepared according to the presentinvention and one or more pharmaceutically acceptable excipients.Depending on the nature of the medical disease or condition to betreated, and the type of patient, the pharmaceutical compositions may beformulated to be delivered by any suitable route, including oral,intravenous, parenteral, inhalation, intranasal, topical, subcutaneous,intramuscular, rectal, vaginal. Suitable dosage forms include knownformulations such as tablets, capsules, powders, sustained releaseformulations, ointments, gels, creams, suppositories, eye drops,transdermal patches, syrups, solutions, suspensions, aerosols, solutionsfor nebulizers, nasal sprays etc. In a preferred embodiment thecomposition is formulated for delivery by the inhalation or intranasalroutes, for instance in an aerosol solution or suspension, as a drypowder for inhalation, or in a nasal spray.

Suitable excipients include carriers, diluents, wetting agents,emulsifying agents, binders, coatings, fillers, glidants, lubricants,disintegrants, preservatives, surfactants, pH buffering substances andthe like. Examples of excipients and their use are provided in theHandbook of Pharmaceutical Excipients, 5^(th) ed. (2006), Ed. Rowe etal., Pharmaceutical Press, which is incorporated herein by reference inits entirety.

The dosages of the compounds of the present invention may depend upon avariety of factors including the particular disease to be treated, theseverity of the symptoms, the route of administration, the frequency ofthe dosage interval, the particular compound utilized, the efficacy,toxicology profile, and pharmacokinetic profile of the compound.

Advantageously, the compounds of formula (I) wherein n is 0 or 1 may beadministered for example, at a dosage comprised between 0.001 and 1000mg/day, preferably between 0.1 and 500 mg/day, even more preferablybetween 0.2 and 2000 mg/day and even more preferably between 0.1 and4000 mg/day.

Compounds of formula (I) wherein n is 0 or 1 obtained according to theinvention may be used for prophylactic purposes or for symptomaticrelief for a wide range of conditions including: respiratory disorderssuch as chronic bronchitis, chronic obstructive pulmonary disease (COPD)and asthma of all types. However the compounds of formula (I) wherein nis 0 or 1 may be administered for the prevention and/or treatment of anydisease wherein the activity of PDE4 receptors is implicated andinhibition of PDE4 receptor activity is desired, or a disease statewhich is mediated by PDE4 activity (for instance a disease state inwhich PDE4 is overexpressed or overactive). Examples of such diseasesinclude: allergic disease states such as atopic dermatitis, urticaria,allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis,eosinophilic granuloma, psoriasis, inflammatory arthritis, rheumatoidarthritis, septic shock, ulcerative colitis, Crohn's disease,reperfusion injury of the myocardium and brain, chronicglomerulonephritis, endotoxic shock, cystic fibrosis, arterialrestenosis, atherosclerosis, keratosis, rheumatoid spondylitis,osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis, toxic andallergic contact eczema, atopic eczema, seborrheic eczema, lichensimplex, sunburn, itching in the anogenital area, alopecia areata,hypertrophic scars, discoid lupus erythematosus, systemic lupuserythematosus, follicular and wide-area pyodermias, endogenous andexogenous acne, acne rosacea, Behcet's disease, anaphylactoid purpuranephritis, inflammatory bowel disease, leukemia, multiple sclerosis,gastrointestinal diseases, autoimmune diseases, and the like.

They also include neurological and psychiatric disorders such asAlzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS),multiple systems atrophy (MSA), schizophrenia, Parkinson's disease,Huntington's disease, Pick's disease, depression, stroke, and spinalcord injury.

In one embodiment, the present invention provides the use of compoundsof formula (I) wherein n is 0 or 1 prepared according to any of themethods of the invention, in the manufacture of a medicament for theprevention or treatment of any of chronic bronchitis, chronicobstructive pulmonary disease (COPD), asthma of all types, atopicdermatitis, and allergic rhinitis.

In a further embodiment, the present invention provides a method forprevention of treatment of any of chronic bronchitis, chronicobstructive pulmonary disease (COPD), asthma of all types, atopicdermatitis and allergic rhinitis in a patient, comprising theadministration to the patient of a therapeutically effective amount ofcompounds of formula (I) wherein n is 0 or 1 prepared according to anyof the methods of the invention.

A “therapeutically effective amount” of substance is defined herein asan amount leading to a detectable improvement in one or more clinicalsymptoms of the treated condition or measurably reducing the probabilityof development of a disease condition or its symptoms.

The present invention is further explained by reference to the followingSchemes 1-6.

The present invention provides a method for preparing a compound ageneral formula (I) wherein n is 0 or 1 according to the followingsteps.

Route A—intermediate (VI) wherein n is 0 or 1, obtained according to theprocedure described in WO 2010/089107, which is incorporated herein byreference in its entirety, Example 1, is oxidized to (VII) wherein n is0 or 1 in presence of an oxidizing agent selected from a metallic oxidesuch as MnO₂, a hypervalent iodine, like 2-Iodoxybenzoic acid (IBX) orDess-Martin periodinate, dimethylsulfoxide-based oxidants (Swern) likeSulfur trioxide pyridine complex. The synthesis is preferably carriedout in a solvent selected from water, dimethyl formamide, dimethylacetamide, N-methyl pyrrolidone, dimethyl sulfoxide, sulfolane, toluene,benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methylisobutyl ketone, ethyl acetate, isopropyl acetate, acetonitrile,dichloromethane, tetrahydrofuran (THF), dioxane and mixtures thereof.The reaction is preferably carried out with MnO₂ in toluene or with aSwern oxidant in DMSO.

Alternatively compound of formula (VII) can be obtained reacting anintermediate of formula B″:

wherein R is a linear or branched (C₁-C₆) alkyl group or a arylalkylgroup, with an intermediate of formula D:

wherein n has the above reported meanings, in presence of a basepreferably selected from lithium diisopropylamide (LDA), butyl lithium,hexyl lithium, pentyl lithium, lithium bis(trimethylsilyl)amide (LHMDS),sodium bis(trimethylsilyl)-amide, and potassium t-butylate, in thepresence of suitable solvents such as toluene, benzene, xylene,tetrahydrofuran, methyl-tetrahydrofuran, dioxane, 2-methoxyethyl ether,diethyl ether, isopropyl ether, t-butylmethyl ether, and mixturesthereof.

More preferably, R is methyl and the above reaction is conducted withLHMDS in THF.

Compound B″ can be obtained from compound B′ by reaction with thionylchloride, hydrochloric acid, sulfuric acid in methanol, ethanol,isopropanol, n-butanol, t-butanol, benzyl alcohol with or without othersolvents, or by reaction with the relative alkyl halide in the presenceof suitable solvents such as methanol, ethanol, isopropanol, n-butanol,t-butanol, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone,tetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate,acetonitrile, dichloromethane, and mixtures thereof and a basepreferably selected from sodium hydroxide, sodium carbonate, sodiumbicarbonate, potassium hydroxide, potassium carbonate, potassiumbicarbonate, lithium hydroxide, lithium carbonate, caesium hydroxide,caesium carbonate, caesium bicarbonate, TEA (triethylamine), DIPEA(Hünig Base, diisopropylethyl-amine), NMM (N-Methylmorpholine), andpyridine.

More preferably, the above reaction is conducted with potassiumcarbonate in dimethyl formamide or dimethyl acetamide.

Compound B′ can be obtained from compound B with an oxidizing agentselected from hydrogen peroxide, an organic peracid, like paraceticacid, or m-chloroperbenzoic acid, or a mineral peracid like persolforicacid, or Oxone® (KHSO₅*½KHSO₄*½K₂SO₄), in the presence of suitablesolvents such as water, methanol, ethanol, isopropanol, n-butanol,t-butanol, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone,tetrahydrofuran, dioxane, 2-methoxyethyl ether, isopropyl acetate,acetonitrile, and mixtures thereof. More preferably, the above reactionis conducted with Oxone® in methanol.

Alternatively intermediate of formula B″ can be obtained fromintermediate of formula C″ by alkylation with Bromo-methylcyclopropanein presence of a base preferably selected from sodium hydroxide, sodiumcarbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate,potassium bicarbonate, lithium hydroxide, lithium carbonate, caesiumhydroxide, caesium carbonate, caesium bicarbonate, TEA (triethylamine),DIPEA (Hünig Base, diisopropylethyl-amine), NMM (N-Methylmorpholine),pyridine, DBU, DBO, and DMAP and in a suitable solvent such as methanol,ethanol, isopropanol, n-butanol, t-butanol, dimethyl formamide, dimethylacetamide, N-methyl pyrrolidone, tetrahydrofuran, dioxane,2-methoxyethyl ether, diethyl ether, isopropyl ether, t-butyl methylether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane,and mixtures thereof. More preferably, the above reaction is conductedwith potassium carbonate in dimethyl formamide.

Intermediate C″ can be obtained from intermediate C′ by Pinner reactionin presence of an alcohol and a Lewis acid selected from hydrogenchloride, hydrogen bromide, sulfuric acid, alkane sulphonic acids likemethane sulfonic acid, aryl sulphonic acids like benzene sulfonic acid,aluminium tribromide, aluminium trichloride, titanium(IV) tetrachloride,Titanium(IV) isopropoxide Tin(IV) chloride, boron trifluoride, Borontrichloride, Iron(III) chloride, Iron(III) bromide, Aluminumisopropoxide, thionyl chloride, oxalyl chloride, trimethylsilyl chloride(TMSCl), and trimethylsilyl triflate (Me3SiOTf), with or without asuitable solvent such as dimethyl formamide, dimethyl acetamide,N-methyl pyrrolidone, toluene, benzene, xylene, tetrahydrofuran,dioxane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, t-butylmethyl ether, and mixtures thereof. More preferably, the above reactionis conducted with sulphuric acid in methanol.

Subsequent enantioselective reduction of (VII) wherein n is 0 or 1provides the single enantiomer (II) wherein n is 0 or 1.

The reducing agent is selected from hydrogen in presence of a heavymetal chiral complex pre-formed or formed in situ reacting a Ru-, Rh- orIr-complex such as RuCl₂(PPh₃)₃, [Ru (p-cymene)Cl₂]₂, [RhCI₂(Cp*)]₂ or[IrCI₂(Cp*)]₂ with a chiral ligand such as SL-N004-1((S)-4-tert-Butyl-2-[(S)-2-(bis(1-phenyl)phosphino)ferrocen-1-yl]oxazoline,),SL-N003-1((R)-4-Isopropyl-2-[(R)-2-(diphenylphosphino)-ferrocen-1-yl]Oxazoline),(S,S)-Ts-DPEN ((1S,2S)-(−)-N-p-tosyl-1,2-diphenylethylenediamine),(S,S)-Ms-DPEN ((1S,2S)-(−)-N-Mesyl-1,2-diphenylethylenediamine),(R)-DAIPEN((2R)-(−)-1,1-Bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine), or (1R,2S)-1-Amino-2-indanol. The reaction is conducted in presence of a base,preferably selected from sodium hydroxide, sodium carbonate, sodiumC₁-C₄ alcoholates, sodium bicarbonate, sodium hydride, potassiumhydroxide, potassium carbonate, potassium C₁-C₄ alcoholates, potassiumbicarbonate, lithium hydroxide, lithium carbonate, lithium C₁-C₄alcoholates, caesium hydroxide, caesium carbonate, caesium bicarbonate,triethyl amine, pyridine, and 4-dimethylaminopyridine.

The synthesis is preferably carried out in a solvent selected fromwater, methanol, ethanol, isopropanol, n-butanol, t-butanol, dimethylformamide, dimethyl acetamide, N-methyl pyrrolidone, toluene, benzene,xylene, THF, dioxane, 2-methoxyethyl ether, diethyl ether, isopropylether, t-butyl methyl ether, ethyl acetate, isopropyl acetate,acetonitrile, and mixtures thereof.

The reaction is preferably carried out with the complex formed in situby reacting RuCl₂(PPh₃)₃ and the chiral ligand SL-N004-1 in toluene inpresence of aqueous sodium hydroxide.

Alternatively, (II) wherein n is 1 is obtained by oxidation of (II)wherein n is 0 with an oxidizing agent selected from hydrogen peroxide,an organic peracid, like paracetic acid, or m-chloroperbenzoic acid, ora mineral peracid like persolforic acid or Oxone® (KHSO₅*½KHSO₄*½K₂SO₄).Reaction solvent is selected from water, methanol, ethanol, isopropanol,n-butanol, t-butanol, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidone, toluene, benzene, xylene, acetone, isopropyl ketone, methylethyl ketone, methyl isobutyl ketone, THF, dioxane, ethyl acetate,isopropyl acetate, acetonitrile, acetic acid, and mixtures thereof. Thereaction is preferably conducted with Oxone® in water and methanol.

Route B—In alternative to Route A, intermediates (II) and (VIII) whereinn is 0 or 1 are obtained from (VI) wherein n is 0 or 1 by preparativechiral HPLC separation of the enantiomers.

A batch procedure may be adopted loading the chiral column with asolution of racemic (VI) in several runs and collecting the elutedfractions of separated enantiomers. A simulated moving bed (SMB)procedure should be considered to separate large amount of material.

Once the compounds of formula (II) and (VIII) have been separatedthrough preparative chiral HPLC techniques, the compound of formula(VIII) may be conveniently reconverted into the compound of formula (VI)through oxidation to the corresponding derivative of formula (VII) andsubsequent reduction and reprocessed in the chromatographic separationprocess, as formerly described.

In this way, by recycling (VIII), final yields of compound of formula(I) can be further increased.

In intermediate (III), wherein X is —NHSO₂Me and Z is selected from —OH,chlorine, bromine, linear or branched (C₁-C₆)alkoxy, aryloxy,arylalkoxy, (C₁-C₆)alkylcarbonyloxy, arylcarbonyloxy andaryl(C₁-C₆)alkylcarbonyloxy, Z is a protecting group that can beintroduced and removed using standard procedures according to“Protective Groups in Organic Synthesis” by Theodora W. Greene(Wiley-Interscience, New York, 1981) and “Protective Groups in OrganicChemistry” by J. F. W. McOmie (Plenum Press, London, 1973), which isincorporated herein by reference in its entirety.

Intermediate (III), wherein X is —NHSO₂Me and Z is as defined above, canbe therefore obtained under well-known conditions starting from3-cyclopropylmethoxy-4-metanesulfonylamino-benzoic acid methyl ester,obtained as described in WO2007/089107, which is incorporated herein byreference in its entirety, Example 18 or according to the same synthesisroute starting from the relative ester of the 3-hydroxy-4-nitrobenzoicacid.

Intermediate (III), wherein X is —NHSO₂Me and Z is as defined above,converts to (III) wherein Z is —OH by hydrolysis in a base, preferablyselected from the group consisting of sodium hydroxide, sodiumcarbonate, potassium hydroxide, potassium carbonate, lithium hydroxide,lithium carbonate, caesium hydroxide, and caesium carbonate; the solventis selected from water alone or in mixture with methanol, ethanol,isopropanol, n-butanol, t-butanol, dimethyl sulfoxide, sulfolane,toluene, benzene, xylene, THF, dioxane, and mixtures thereof. In apreferred embodiment the reaction is carried out with NaOH in THF andwater.

Route C—compound (I) wherein n is 0 or 1 is obtained by condensingintermediate (III) wherein X is —NHSO₂Me and Z is —OH, with (II) whereinn is 0 or 1 in presence of a coupling reagent selected from CDI(1,1′-Carbonyldiimidazole), HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate), HBTU(O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate), TBTU(O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate),DMTMM (4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride), COMU((l-Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate), EDCI(N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride), and DCC(N,N′-Dicyclohexylcarbodiimide), or a reagent that can convert thecarboxylic acid into a acyl chloride, an acyl bromide, an activate esteror a mixed anhydride, with or without HOBt (1-Hydroxybenzotriazole),with or without an organic base like TEA, DIPEA, NMM, DBU, DBO,pyridine, and DMAP in a solvent selected from the group consisting ofdimethyl sulfoxide, sulfolane, dimethyl formamide, dimethyl acetamide,N-methyl pyrrolidone, toluene, benzene, xylene, acetone, isopropylketone, methyl ethyl ketone, methyl isobutyl ketone, THF, dioxane,2-methoxyethyl ether, diethyl ether, isopropyl ether, t-butyl methylether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane,chloroform, chlorobenzene, and mixtures thereof.

When the compound of formula (III) is an acyl chloride or bromide, or anactivated ester and a mixed anhydride, the reaction is carried out asabove described without the presence of a coupling reagent.

In a preferred embodiment the reaction is conducted with CDI and DBU inethyl acetate.

Intermediate (IV), wherein n is 0 or 1, is obtained by condensation of(III) wherein X is —NO₂, with (II) wherein n is 0 or 1, under the sameconditions described above for the condensation of (III) wherein X is—NHSO₂Me with (II). In a preferred embodiment the reaction is conductedwith EDCI and DMAP in DMF.

Intermediate (V), wherein n is 0 or 1, is obtained by reducing (IV),wherein n is 0 or 1, with a reducing agent selected from the groupconsisting of hydrogen, cyclohexadiene, ammonium formate, formic acid,iron, tin dichloride, tin, nickel chloride, nickel, lithium aluminiumhydride, sodium aluminium hydride, lithium borohydride, sodiumborohydride, and potassium borohydride sodium hydrosulfite. In the caseof the employment of hydrogen, cyclohexadiene, ammonium formate, andformic acid the reaction is carried out in the presence of a catalyst,preferably palladium-platinum- or nickel-based, more preferably selectedfrom palladium on carbon, palladium on barium sulphate, and palladium oncalcium carbonate. When formic acid is used, the reaction is carried outin the presence of ammonia or an amine, preferably triethylamine.

Suitable solvents for the above reducing steps are selected from water,methanol, ethanol, isopropanol, n-butanol, t-butanol, dimethylformamide, dimethyl acetamide, N-methyl pyrrolidone, toluene, benzene,xylene, THF, dioxane, 2-methoxyethyl ether, diethyl ether, isopropylether, t-butyl methyl ether, ethyl acetate, isopropyl acetate,acetonitrile, and mixtures thereof. In a preferred embodiment thereaction is carried out with hydrogen with palladium 5% on activatedcarbon powder, type A103038, sulfided in ethyl acetate.

In another preferred embodiment, the reaction is carried out withhydrogen with platinum on charcoal in ethyl acetate.

Compound (I), wherein n is 0 or 1, is obtained by reacting (V), whereinn is 0 or 1, with methanesulfonyl chloride in the presence of suitablesolvents selected from toluene, benzene, xylene, tetrahydrofuran,dioxane, 2-methoxyethyl ether, diethyl ether, isopropyl ether,t-butylmethyl ether, ethyl acetate, isopropyl acetate, acetonitrile,dichloromethane, chloroform, chlorobenzene, and mixtures thereof and abase preferably selected from the group consisting of sodium hydroxide,sodium carbonate, sodium bicarbonate, sodium hydride, potassiumhydroxide, potassium carbonate, potassium bicarbonate, lithiumhydroxide, lithium carbonate, caesium hydroxide, caesium carbonate,caesium bicarbonate, TEA (triethylamine), DIPEA (Hünig Base,diisopropylethyl-amine), NMM (N-Methylmorpholine) DBU(1,8-Diazabicyclo[5.4.0]undec-7-ene), DBO(1,4-Diazabicyclo[2.2.2]octane), pyridine, and DMAP(4-dimethylaminopyridine), pyridine; in the case when pyridine is usedin excess other solvents can be avoided.

The reaction is preferably carried out with triethylamine indichloromethane.

All the compounds of formula (I), (II), (IV), (V), (VI), (VII) or (VIII)wherein n is 1 can be obtained by oxidizing the corresponding compoundswherein n is 0, as described above for the oxidation of compound (II)wherein n is 0 to compound (II) wherein n is 1.

When compound (I) wherein n is 0 or 1 is obtained, it may be purified bycrystallization or crushing from one or more solvents preferablyselected from water, methanol, ethanol, isopropanol, n-butanol,t-butanol, toluene, benzene, xylene, acetone, isopropyl ketone, methylethyl ketone, methyl isobutyl ketone, THF, dioxane, 2-methoxyethylether, diethyl ether, isopropyl ether, t-butyl methyl ether, ethylacetate, isopropyl acetate, dichloromethane, an aliphatic or aromatichydrocarbon, preferably chosen from the group consisting in pentane,hexane, heptane, cyclohexane and methylcyclohexane or mixture thereof.The reaction is preferably carried out in ethyl acetate with n-heptane.

Thus, for example, Crystalline Form A may be prepared in presence ofethyl acetate/heptane, or isopropyl acetate.

The reaction may be carried out in a reactor, wherein compound offormula (I) is loaded together with one or more solvents selected fromthe above list, and the suspension may be stirred while heating to atemperature between 50 to 90° C. until complete dissolution of thesolid. The suspension may be cooled down between 0 to 5° C. for 1 to 5hours, filtered and dried.

When the crystallization is carried out in presence of ethanol, asolvate of compound of formula (I) may be obtained.

The reaction may be carried out starting from a compound of formula (I),in one or more solvents selected from the group consisting of pentane,hexane, heptane, cyclohexane, methylcyclohexane and dichloromethane,obtaining a solution that may be concentrated and then added withethanol. The solution may be concentrated and the obtained suspensionmay be cooled at a temperature between 0 to 10° C. and stirred for 1 to5 hours. The solid filtered, washed with ethanol and dried at atemperature between 25 to 55° C. for 10 to 30 hours.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1. Preparation of3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoic acid (Intermediate(III), X=—NHSO₂Me, Z=—OH)

(III) Wherein X is —NHSO₂Me and Z is —OMe was obtained as described inWO 2010/08910, which is incorporated herein by reference in itsentirety, Example 18. It (6.0 kg) and 18 L of THF were loaded into areactor. Separately, 6.6 kg of 35% w/w sodium hydroxide and 21 L ofpurified water were mixed and transferred into the reactor, and themixture was heated up to 65° C. while distilling off all the THF. Afterthe completion of the hydrolytic reaction the basic solution was slowlytransferred into another reactor containing a solution of 24 L ofpurified water and 7.2 kg of 37% w/w hydrochloric acid, keeping thetemperature below 40° C. and stirring for 15 minutes. The obtained solidwas filtered and washed with 24 L of water. The wet solid (III) (16.6 kgwet) was reloaded in the reactor together with 60 L of ethyl acetate,then heated up to reflux to distill off 30 L of solvent. 12.6 L ofheptane were loaded in the reactor and the mixture was kept understirring for 15-30 minutes. It was then cooled down to 5° C. and keptunder stirring for 2 hours. The obtained solid was filtered and thereactor and the cake washed with 12 L of heptane. Wet solid was driedunder vacuum in a static tray drier. 6235 g of white solid were obtained(93.9% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.85 (br. s., 1H), 9.03 (s, 1H),7.40-7.71 (m, 2H), 7.35 (d, J=8.16 Hz, 1H), 3.91 (d, J=6.84 Hz, 2H),3.07 (s, 3H), 1.11-1.42 (m, 1H), 0.50-0.67 (m, 2H), 0.18-0.41 (m, 2H).

Example 2. Preparation of1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)ethanone(Intermediate (VII), n=0)

Intermediate (VI) wherein n is 0 was obtained according to themanufacturing procedure described in WO 2010/089107, which isincorporated herein by reference in its entirety, Example 1.

Alternative Procedures to Obtain Intermediate (VII), n=0:Procedure with MnO₂

5 kg of (VI) wherein n is 0, were dissolved in 30 L of toluene in areactor, 3.15 kg of activated MnO₂ were added into the organic mixture,and the suspension was heated up to reflux for 3 hours. The mixture wascooled down to 50° C. and MnO₂ was filtered off on celite pad. Theorganic solution was loaded in a reactor and toluene was distilled offtill to 3 residual volumes. 20 L of 2-propanol was added into reactorand concentrated again till to 2 residual volumes, in order to removethe entire quantity of toluene. Further 20 L of 2-propanol were loadedand the solvent was partially distilled to have 4 residual volumes inthe reactor. The suspension was cooled down and kept under stirring at10° C. overnight. The solid was filtered and the wet solid dried in avacuum oven at T=50° C. for 12 hours obtaining a white solid (4.12 kg,82.8% yield).

Product characterization is described in WO 2009018909, which isincorporated herein by reference in its entirety, Example 2(Intermediate 1b).

Procedure Swern

Triethylamine (4.5 mL, 32 mmol) was added dropwise to a solution ofalcohol (VI) wherein n is 0, (5.0 g, 12.4 mmol) in DMSO (15 mL),stirring at 25° C. Pyridine. SO₃ complex (5.0 g, 31 mmol) is addedportionwise in about 1 hr, so that the internal batch temperature doesnot rise above 35° C. The reaction mixture is stirred at 25° C. for 4hours and then quenched with water (60 mL) and 10% aq. H₂SO₄ 10% (10mL). The resulting mixture is stirred at 25° C. and the solid filteredoff and desiccated at 50° C. under reduced pressure, to afford 4.6 g(92% yield) of pure ketone (VII) as a colorless solid.

Procedure with IBX

(VI) Wherein n is 0, (1.0 g, 2.5 mmol) was added in a single portion toa suspension of 2-Iodoxybenzoic acid (IBX) (0.9 g, 3.2 mmol), preparedaccording to literature (JOC 1999 pg 4537, which is incorporated hereinby reference in its entirety), in DMSO (5 mL), and the resulting mixturewas stirred at 25° C. for 1 hour and then to 50° C. for 2 hours. Thereaction was quenched with a 10% aq. solution of potassium carbonate (40mL) after cooling to 25° C. and the solid filtered off to afford ketone(VII) in quantitative yield.

Procedure with sIBX®

Commercially available sIBX® (“Stabilized IBX”, a white-powderformulation of IBX composed of a mixture of benzoic acid (22%),isophthalic acid (29%), and o-iodoxybenzoic acid (49%) from SIMAFEX)(2.0 g, 3.2 mmol) was added in a single portion to a solution of (VI)wherein n is 0 (1.0 g, 2.5 mmol) in acetone (15 mL) at 25° C., theresulting mixture was refluxed for 2.5 hours, cooled at 25° C. and thenquenched with a 10% aq. solution of sodium sulfite (10 mL) and a 10% aq.solution of potassium carbonate (40 mL). The mixture was stirred at 25°C. for 0.5 hours and the solid filtered off, to afford ketone (VII)wherein n is 0 in quantitative yield.

Procedure with DMP

Dess-Martin periodinane (DMP) (1.3 g, 0.31 mmol) was added in a singleportion to a solution of alcohol (VI) wherein n is 0 (1.0 g, 2.5 mmol)in acetone (5 mL). The reaction mixture was stirred at 25-30° C. for 1hour and quenched with a 10% aq. solution of sodium metabisulfite (10mL) and 15% aq. sol. of potassium carbonate (30 mL). The mixture wasstirred at 25° C. for 0.5 hours and the solid filtered off to afford(VII) wherein n is 0 in quantitative yield.

Example 2A. Preparation of 3,5-dichloro-4-methyl-1-oxy-Pyridine(Intermediate A)

3,5-Dichloro-4-methyl-Pyridine (0.5 g, 3.08 mmol) and Oxone® (1.5 g,4.62 mmol) were suspended in a 8:3 mixture of methanol and water (5.5ml) in a 25 ml flask. The suspension was stirred and warmed to 55° C.for 10-15 hours. The solvent was removed under reduce pressure and theobtained crude solid was suspended under stirring in hot Toluene (80°C.) for 20 minutes. The heterogeneous hot solution was then filtratedand the mother liquors were cooled to room temperature obtaining theprecipitation of a solid. The pure product was obtained as a white solidafter stirring at 0-5° C. for 30 minutes and filtration (0.43 g, 78%yield).

Example 2B. Preparation of(R/S)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)ethanol(Intermediate (VI), n=1)

In a three necked 50 ml flask under nitrogen atmosphere Intermediate A(0.4 g, 2.25 mmol) and Intermediate B (0.78 g, 3.22 mmol) were added,and dissolved in dry THF (5 ml). The stirred solution was cooled to −35°C. Potassium tert-butylate (0.3 g, 2.67 mmol) was added portionwise tothe solution in 10 minutes. After 60 minutes of reaction at −35° C., thesolution is quenched with a 25% aqueous solution of NH4Cl (10 ml). EtOAc(8 ml) and water (8 ml) were added to the suspension and stirred, phaseswere separated and the organic phase was extracted and washed with a 5%aqueous solution of NaCl (10 ml). The organic solvent was thenanydrified on Na2SO4 and removed under reduced pressure obtaining acrude white solid. This was crystallized from hot Toluene obtaining awhite solid (0.40 g, 42% yield).

Example 3. Preparation of(R)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl)ethanol(Intermediate (II), n=0)

2.40 kg of (VII) wherein n is 0 were dissolved in 23 L of toluene in areactor. The reactor was degassed with nitrogen. Solvias proprietaryligand SL-N004-1 and RuCI2(PPh3)3 were placed in a 2 L Schlenk bulb anddried and degassed toluene (1.2 L) was charged. The mixture was heatedto 80° C. for 1 hour and then allowed to reach room temperature (RT).The catalyst solution and 298 mL of a degassed aqueous 0.5 M NaOHsolution were subsequently added to the reactor. The reactor was closedand degassed with nitrogen and set under 10 bar hydrogen. The mixturewas heated to 35° C. under a constant pressure of 10 bars. After a totalreaction time of 19 hours, the heater was switched off. The reactor wascooled down to RT and the aqueous layer was removed. The organic phasewas washed twice with 0.5 L of water; aqueous phase was back extractedwith 1 L of toluene that was added to the organic phase. 240 g ofdecolorizing carbon (Norit CAP Super) were added to the toluenesolution, and the mixture was stirred at RT overnight. The carbon wasfiltered off and the filter cake was rinsed with 1.5 L Ethyl acetate.The yellowish solution was concentrated to dryness at reduced pressureto yield 2.38 kg of crude wet material. It was dissolved in 1.5 L ofisopropyl acetate at 60° C. under stirring, 9 L of preheated heptane(50° C.) were added, and the mixture was stirred at 60° C. The solutionwas seeded and slowly cooled to RT under stirring. Stirring wascontinued at room temperature overnight, then the mixture was cooled to0° C. for 1 hour. The solid was filtered and dried. The yield was 2.1 kg(87% yield, 95.0% ee).

Example 4. Separation of(R)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)ethanoland(S)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)ethanol(Intermediates (VIII) and (II), n=0)

Chromatographic separation was performed on 3000 g of (VI) wherein n is0, in batch using a Chiralpak IC 20 μm-250*76 mm column anddichloromethane/ethanol 95/5 v/v as mobile phase. A solution of racemic(VI) was loaded in several runs at the top of the chiral column and theeluted fractions of the separated enantiomers collected at the bottom ofthe column were gathered. (II) Was crystallized from the concentratedDCM/EtOH elution mixture enriched in ethanol. 1440 g (48% yield) of thedesired enantiomer (II) wherein n is 0 with HPLC purity>99.5% and HPLCchiral purity>99.5% were obtained. 1470 g (49% yield) of the otherenantiomer (VIII) wherein n is 0 with HPLC purity>99% and HPLC chiralpurity>99% were also obtained.

Example 4A. Separation of(R)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)ethanoland(S)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)ethanol(Intermediates (VIII) and (II), n=1)

In analogy with Example 4 chromatographic separation using a ChiralpakIC 20 μm-250*76 mm column and methanol as mobile phase can be performedon a solution of racemic (VI) wherein n is 1, to obtain the desiredenantiomer (II) wherein n is 1 with high HPLC purity and HPLC chiralpurity. The other enantiomer (VIII) wherein n is 1 with high HPLC purityand HPLC chiral purity can also be obtained.

Example 5. Preparation of(S)-3-Cyclopropylmethoxy-4-methanesulfonylaminobenzoicAcid-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)-ethylester (Compound (I), n=0)

75 g of (III) wherein X is —NHSO₂Me and Z is —OH, were suspended in 750ml of DCM; 42.5 g of N,N-carbonyldiimidazole were added portion-wise andthe obtained solution was stirred at RT for 30 minutes. 375 ml ofToluene were added, followed by 85 g of (II) wherein n is 0 and themixture was heated up to reflux. DCM was removed by distillation, thenthe suspension was stirred at 100° C. overnight. The obtained solutionwas cooled to 40° C., added with 500 ml of Ethyl acetate and washed withNaHCO₃ solution and brine. The product was isolated by crystallizationfrom Ethyl acetate/Heptane, and re-crystallized with the same solventmixture to obtain a white solid (recovery 129 g, 73% yield).

Product characterization is described in WO 2010089107, which isincorporated herein by reference in its entirety, Example 15.

Example 6. Preparation of(S)-3-Cyclopropylmethoxy-4-methanesulfonylaminobenzoicAcid-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester (Compound (I), n=1)

Procedure with H₂O₂/Acetic Acid.

73 g of (I) wherein n is 0, were charged in a flask, followed by 150 mlof toluene and 290 ml of acetic acid and 75 ml of 35% H₂O₂ and themixture was heated up to 80° C. for 8 hours. The mixture was cooled downto 50° C., 750 ml of ethyl acetate were added, and the aqueous phaseremoved; the organic phase was washed with water and a 10% NaHCO₃aqueous solution to an alkaline pH, and the solvent was removed bydistillation. The crude material was purified by crystallization from375 ml of ethyl acetate and 225 ml of n-heptane and dried in a statictray drier to obtain a white solid (recovery 65.1 g, 87.1% yield).

Product characterization is described in WO 2010089107, which isincorporated herein by reference in its entirety, Example 17.

Example 7. Preparation of(S)-(3-Cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethanol(Intermediate (II), n=1)

Procedure with H₂O₂/Acetic Acid.

490 g of (II) wherein n is 0, were loaded into a reactor together with1960 ml of glacial acetic acid. The mixture was heated up to 50° C. thengradually 980 ml of hydrogen peroxide 30 to 35% in water were added andthe mixture was kept under stirring at the same temperature for 16hours. 2000 ml of purified water were slowly added and (II) wherein n=1precipitated as a solid. The slurry was cooled down to 10° C. and keptunder stirring for 3 hours. The solid was then filtered off and theobtained solid was washed with 1000 ml of water. The wet solid (II)wherein n is 1 was re-suspended in 2000 ml of water for 2 hours and in2000 ml of diisopropyl ether for 3 hours. The wet solid was dried undervacuum. 433 g of white solid were obtained (85% yield).

Product characterization is described in WO 2010089107 which isincorporated herein by reference in its entirety, Example 7.

Procedure with Oxone®.

456 g of Oxone® (KHSO₅*½KHSO₄*½K₂SO₄) and 1.2 L of water were added in areactor and the mixture was stirred at RT. 400 g of (II) wherein n is 0,and 3.2 L of methanol were added and the mixture was heated up to 70° C.for 3 hours. Further 50 g of Oxone® were added and after 1.5 hours, thereaction was completed. The alcohol was distilled off and 4 L of waterand 2 L of ethyl acetate were added at 50° C. The aqueous phase wasdischarged and the organic phase was washed with 800 ml of water andconcentrated under vacuum to 1.5 L. 4 L of toluene were added, and themixture was concentrated under vacuum to 2.5 L while the productprecipitation initiated. The suspension was cooled down to 10° C. andkept under stirring for 1.5 hours. The obtained solid was filtered andwashed with 800 ml of toluene. Wet solid was dried under vacuum in astatic tray drier. 288 g of white solid were obtained (72% yield).

Product characterization is described in WO 2010089107 which isincorporated herein by reference in its entirety, Example 7.

Example 8. Preparation of(S)-3-Cyclopropylmethoxy-4-methanesulfonylaminobenzoicAcid-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester (Compound (1), n=1)

100 g of (III) wherein X is NHSO₂Me and Z is —OH and 1 L of ethylacetate were loaded in a reactor. 57 g of Carbonyldiimidazole were addedportion-wise under stirring at 40° C., then the mixture was stirred for60 minutes. 123 g of (II) wherein n=1 and 3.7 ml of1,8-Diazabicyclo[5.4.0]undec-7-ene were added, and the mixture washeated up to 75° C. for approximately 4 hours. The organic solution waswashed with 500 ml of 1M HCl in water, with 500 ml of 5% NaHCO₃ aqueoussolution and with 500 ml of 10% NaCl aqueous solution. The organicmixture was heated up to 70° C. under vacuum and concentrated to 600 ml.The mixture was cooled down to 50° C. and 300 ml of n-heptane wereadded. The solution was seeded, cooled down to 5° C. and kept understirring for 1.5 hours. The obtained solid was filtered off and driedunder vacuum. 168 g of crude solid were obtained (82% yield).

Product characterization is described in WO 2010089107 which isincorporated herein by reference in its entirety, Example 17.

Example 9. Preparation of(S)-3-Cyclopropylmethoxy-4-methanesulfonylamino-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester (Compound (I), n is 1)—Solvated from Ethanol

A solution of crude compound (I) wherein n is 1 was loaded in a ILreactor. DCM (90 ml) and EtOH (300 ml) were added, the white suspensionwas stirred and warmed to reflux until complete dissolution. The DCM wasdistilled off and a white solid started to precipitate. The ethanolicsolution was further concentrated to 6 to 7 volumes distilling off partof the EtOH and then cooled down to 0 to 5° C. and stirred for 120minutes. The obtained solid was filtered and washed with 30 ml of EtOH.Wet solid was dried under vacuum in a static tray drier. 28.55 g ofwhite solid were obtained (95% yield).

The compound of formula (I) wherein n is 1 obtained as solvate as perExample 9, was investigated to determine the melting point byDifferential Scanning Calorimetry (DSC), Raman spectroscopy to observevibrational, rotational and low-frequency modes and the X-ray powderdiffraction (XRPD) pattern.

It is characterized by:

a melting range of 87° to 101° C. determined by DSC at a scan rate of10° C./min.;

a X-ray powder diffraction pattern characterized by the following XRPDpeaks (Bruker D8 Advance con Xray Diffraction Tube type KFL CuKα2):7.45; 7.87; 8.51; 10.12; 10.28; 12.66; 13.29; 13.45; 14.95; 16.14;16.34; 17.05; 17.74; 18.05; 18.48; 18.88; 19.05; 19.33; 19.85; 20.18;20.65; 21.3; 22.96; 23.55; 23.87; 24.41; 24.66; 24.88; 25.62; 25.82;26.45; 28.12 and 28.53±0.2 degrees/2 theta.

Example 10. Crystallization of Compound (I) Wherein n is 1—Form A

Procedure from Ethyl Acetate/Heptane

5 g of crude (I) wherein n is 1 were loaded in a reactor together with30 ml of ethyl acetate and the suspension was stirred while heating to75° C. until complete dissolution of the solid. 15 ml of n-heptane wereadded and the solution was allowed to reach RT. The suspension wascooled down to 5° C. for 2 hours, filtered and dried under vacuum. Awhite solid, the so-called Form A, was obtained (3.6 g, 72% yield).

The compound of formula (I) wherein n is 1 obtained as Form A as perExample 10, was investigated to determine the melting point byDifferential Scanning Calorimetry (DSC), Raman spectroscopy to observevibrational, rotational and low-frequency modes and the X-ray powderdiffraction (XRPD) pattern.

It is characterized by:

a melting range of 144°-147° C. determined by DSC at a scan rate of 10°C./min.;

a X-ray powder diffraction pattern characterized by the following XRPDpeaks (Bruker D8 Advance con Xray Diffraction Tube type KFL CuKα2):7.48; 7.93; 8.55; 10.15; 10.32; 12.72; 13.51; 16.18; 16.46; 17.79;18.08; 18.53; 18.94; 19.1; 19.89; 20.2; 21.37; 22.96; 23.63; 24.87;25.82; 26.51; 28.09; and 28.61±0.2 degrees/2 theta.

Procedure from Isopropyl Acetate

5 g of crude (I) wherein n is 1 were loaded in a flask with 20 ml ofisopropyl acetate and the suspension was heated to reflux until completedissolution. The mixture was cooled down to 0° C. and stirred for 2hours. The obtained solid was filtered and washed with 10 ml ofisopropyl acetate. The wet solid was dried under vacuum. 4.05 g of whitesolid, the crystalline Form A, was obtained (81% yield).

Product characterization is described in WO 2010089107, which isincorporated herein by reference in its entirety, Example

Example 11. Oxidation of Intermediate (VII), n=0 to1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)ethanone(Intermediate (VII), n=1)

Procedure with H₂O₂/Acetic Acid.

0.5 g of (VII) wherein n is 0 were loaded into a 50 ml flask togetherwith 3 ml of glacial acetic acid. The homogeneous solution was heated upto 50° C. then gradually 1 ml of hydrogen peroxide 30 to 35% in waterwas added, and the mixture was kept under stirring at the sametemperature for 21 hours. Then solvent was removed under reducedpressure and the crude solid purified on column chromatography with agradient elution (Hexane/EtOAc 85/15 to EtOAc 100%), yielding the pureproduct as a white solid. (yield 50%).

Procedure with Oxone®.

10 g of (VII) wherein n is 0 were loaded into a flask together with11.44 g of Oxone®, 80 ml of methanol and 30 ml of water. The mixture washeated up to 65° C. for 5 hours and at RT for 48 hours. The alcohol wasdistilled off and 50 ml of water and 100 ml of toluene were added. Themixture was heated until complete dissolution of the solid, the aqueousphase discharged and the organic phase was concentrated under vacuum to70 ml. The suspension was cooled down to 0° C. and kept under stirringfor 1.5 hours. The obtained solid was filtered off and dried undervacuum in a static tray drier. 6.7 g of white solid were obtained (60%yield).

Procedure with MCPBA.

0.5 g of (VII) wherein n is 0 were dissolved in 10 ml of THF, 0.34 g ofMCPBA (3-Chloroperoxybenzoic acid, 77% assay) were added, and themixture was stirred at RT overnight. HPLC control confirmed almostcomplete conversion. The solution was partitioned between 100 ml ofethyl acetate and 50 mo of a aqueous 5% solution of potassiumhydrogencarbonate. The organic phase was washed with further 50 ml ofbasic solution and dried under vacuum. The crude was purified on silicapad with a mixture of ethyl acetate and dichloromethane as eluent. 0.22g of (VII) wherein n=1 were obtained (42% yield).

Example 12. Oxidation of Intermediate (VI), n=1 to1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)ethanone(Intermediate (VII), n=1)

Procedure with DMP.

Alcohol (VI) wherein n is 1 (1.0 g, 2.38 mmol) was suspended in acetone(15 ml). The suspension was cooled under stirring at 0 to 5° C. with anice-bath. Dess-Martin periodinane (1.4 g, 3.3 mmol) was then added in asingle portion. The reaction was initially exothermic and after 1 hourit was left to reach RT. After 20 hours, the reaction went to completionand was quenched with 10 mL of a 10% aq. Sodium metabisulfite solutionand 30 mL of 15% potassium carbonate aqueous solution were added. Themixture was stirred at 25° C. for 0.5 hours, and the solid filtered toafford ketone (VII) wherein n is 1 in quantitative yield.

Example 13. Preparation of 3-(cyclopropylmethoxy)-4-nitrobenzoic acid(Intermediate (III), X=—NO₂ and Z=—OH)

(III) Wherein X is —NO₂ and Z is —OMe was prepared according to theprocedure described in WO 2010/089107, which is incorporated herein byreference in its entirety, Example 18. 550 g of (III) wherein X is —NO₂and Z is —OMe were loaded in a reactor, followed by 1.65 L of THF and2.85 L of a 1 M aqueous solution of lithium hydroxide. The mixture washeated up to 40° C. for 1.5 hours, then cooled to RT. 4.4 L of ethylacetate were added, followed by 240 ml of HCl 37% aqueous solution. Theaqueous phase was discharged and the organic phase was washed twice with2.75 L of water and then concentrated under vacuum at 50° C., 1.65 L ofn-heptane were added at the same temperature, and the suspension wascooled down to RT. The solid was filtered off and dried in a vacuum traydrier obtaining 337 g of (III) wherein X is —NO₂ and Z is —OH (73%yield).

Example 14. Preparation of (S)-3-Cyclopropylmethoxy-4-nitrobenzoicAcid-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)-ethylester (Intermediate (IV), n=0)

Intermediate (III) wherein X is —NO₂, Z is —OH (80 g, 0.34 mol, ref.)and (II) wherein n is 0 (109.1 g, 0.27 mol, 0.9 eq), EDC.HCl (193.9 g,1.01 mmol, 3 eq), DMAP (20.6 g, 0.17 mol, 0.5 eq) and DMF (400 ml, 5vol) were mixed together and heated to 75° C. overnight. The solutionwas partitioned between water and ethyl acetate, the organic phase iswashed with acidic and basic aqueous solution and concentrated undervacuum. The crude material was crystallized with EtOH (1200 ml), acetone(100 ml). A white solid was obtained (101 g, 60% yield respect to(VIII)).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.60 (s, 2H), 7.97 (d, J=8.38 Hz, 1H),7.61-7.80 (m, 2H), 7.18-7.32 (m, 2H), 7.02-7.14 (m, 2H), 6.27 (dd,J=9.70, 3.97 Hz, 1H), 4.04-4.21 (m, 2H), 3.89-4.02 (m, 2H), 3.74 (dd,J=14.11, 9.70 Hz, 1H), 3.45 (dd, J=13.89, 4.19 Hz, 1H), 1.10-1.30 (m,2H), 0.49-0.65 (m, 4H), 0.36 (qd, J=5.44, 5.29 Hz, 4H).

Example 15. Preparation of (S)-3-Cyclopropylmethoxy-4-nitrobenzoicAcid-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester (Intermediate (IV), n=1)

(III) Wherein X is —NO₂ and Z is —OH (80 g, 0.34 mol, ref.), (II)wherein n is 1 (113.9 g, 0.27 mol, 0.9 eq), EDC.HCl (193.9 g, 1.01 mmol,3 eq), DMAP (20.6 g, 0.17 mol, 0.5 eq) and DMF (400 ml, 5 vol) weremixed together and heated to 100° C. overnight. The solution waspartitioned between water and ethyl acetate, the organic phase waswashed with acidic and basic aqueous solution and concentrated undervacuum. The crude material was crystallized with EtOH (600 ml), acetone(200 ml) and heptane (200 ml). A white solid was obtained (71 g, 41%yield respect to intermediate (II) wherein is 1).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.56 (s, 2H), 7.97 (d, J=8.38 Hz, 1H),7.62-7.83 (m, 2H), 7.16-7.32 (m, 2H), 7.04-7.14 (m, 2H), 6.20 (dd,J=9.26, 4.41 Hz, 1H), 4.11 (dd, J=7.06, 3.53 Hz, 2H), 3.93 (d, J=6.62Hz, 2H), 3.62 (d, J=9.26 Hz, 1H), 3.32 (d, J=9.26 Hz, 1H), 1.17-1.26 (m,2H), 0.49-0.67 (m, 4H), 0.24-0.43 (m, 4H).

Example 16. Preparation of (S)-3-Cyclopropylmethoxy-4-aminobenzoicAcid-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)-ethylester (Intermediate (V), X=NH₂ and n=0)

Hydrogenation Procedure.

The reactor was charged with 2.5 g of (IV) wherein n is 0, 119 mg ofPd/C catalyst and 25 ml of ethyl acetate. The reactor was then sealedand heated up under mild stirring to the internal temperature of 40° C.The reactor was charged with hydrogen at 4 bars. After 4 hours theconversion was complete. The catalyst was removed by filtration and thesolvent distilled under reduced pressure. 2.20 g of product wererecovered (90% yield).

¹H NMR (400 MHz, CDCl3) δ ppm 8.50 (s, 2H), 7.49-7.56 (m, 1H), 7.30-7.36(m, 2H), 7.10-7.19 (m, 1H), 7.00-7.08 (m, 2H), 6.58-6.68 (m, 1H),6.20-6.28 (m, 1H), 4.11 (bs, 2H), 3.78-3.92 (m, 4H), 3.69-3.79 (m, 1H),3.30-3.37 (m, 1H), 1.178-1.32 (m, 2H), 0.58-0.71 (m, 4H), 0.28-0.35 (m,4H).

Procedure with SnCl₂.

2 g of (IV) wherein n is 0 was dissolved in 20 ml of THF and 4.34 g ofTin(II) chloride dihydrate were added. The solution was stirred at 80°C. overnight. The solution was partitioned between 100 ml of ethylacetate and 100 ml of a 5% aqueous solution of KHCO₃. The mixture wasfiltered to remove the precipitated salts and the aqueous phase wasdischarged. The organic phase was washed with further KHCO₃ and brine.The organic solvent was removed under vacuum isolating (V) wherein n is0 as a yellow oil (1.84 g, 97% yield).

Example 17. Preparation of (S)-3-Cyclopropylmethoxy-4-aminobenzoicAcid-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester (Intermediate (V), n=1)

Hydrogenation Procedure.

The reactor was charged with 400 mg of (IV) wherein n=1, 8 mg of 1% Pt/Ccatalyst, and 4 ml of ethyl acetate, sealed and heated up under mildstirring to 60° C., charged with hydrogen at 4 bar and stirring wascontinued for 4 hours. The mixture was filtered to remove the catalystand dried under vacuum.

Procedure with SnCl₂.

1 g of (IV) wherein n=1 was dissolved in 10 ml of THF and 1.06 g ofTin(II) chloride dihydrate were added. The solution was stirred at RTovernight. The solvent was evaporated under vacuum and 10 ml of ethylacetate and 10 ml of a 1M aqueous solution of NaOH were added to thecrude. The aqueous phase was discharged and the organic phase was washedwith 10 ml of a 10% aqueous solution of NaCl. The organic solvent wasremoved and the crude was suspended in diethyl ether and stirred until asolid was obtained; it was filtered, washed with 4 ml of diethyl etherand dried in a static tray drier. A white solid was obtained (0.68 g,71.3%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.55 (s, 2H), 7.40 (dd, J=8.38, 1.76 Hz,1H), 7.28 (d, J=1.76 Hz, 1H), 7.15-7.21 (m, 2H), 6.99-7.08 (m, 2H), 6.64(d, J=8.38 Hz, 1H), 6.14 (dd, J=9.59, 4.30 Hz, 1H), 5.63 (s, 2H),3.88-3.96 (m, 2H), 3.70-3.88 (m, 2H), 3.55 (dd, J=14.11, 9.92 Hz, 1H),3.24-3.31 (m, 1H), 1.11-1.34 (m, 2H), 0.47-0.65 (m, 4H), 0.19-0.41 (m,4H).

Example 18. Preparation of(S)-3-Cyclopropylmethoxy-4-methanesulfonylamino-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethylester (Compound (I), n=0)

0.5 g of (V) wherein n is 0 (0.84 mmol) were dissolved in DCM (7 ml) andTEA (0.17 ml, 1.26 mmol), then methanesulfonyl chloride (0.11 g, 0.93ml) was slowly added, and the solution stirred at RT for 20 hours. Thereaction was then quenched with water (20 ml) and the organic solventextracted and washed with a NaCl 5% aqueous solution (10 ml). Thesolvent was removed and the crude purified on column chromatography witha gradient elution (hexane 100% to hexane/EtOAc 60/40), yielding thepure product as a colorless oil (yield 30%).

Example 19. Oxidation of Intermediate (IV) wherein n is 0 to Obtain(S)-3-Cyclopropylmethoxy-4-nitrobenzoicAcid-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester (Intermediate (IV), n=1)

Procedure with H2O2/Acetic Acid.

0.5 g of (IV) wherein n is 0 were loaded into a 50 ml flask with 3 ml ofglacial acetic acid. The solution was heated up to 55° C., thengradually 1 ml of hydrogen peroxide (35%) was added and the mixture waskept under stirring at the same temperature for 48 hours. 5 ml of waterwere added, the product was extracted with ethyl acetate and the organicsolvent was removed under reduced pressure yielding the product as ayellow oil (yield 74%).

Procedure with Oxone®.

0.3 g of (IV) wherein n is 0 were charged in a 50 ml flask, followed by2.4 ml of Methanol, 1 ml of water and 215 mg of Oxone®. The suspensionwas stirred at 55° C. for 48 hours and at 40° C. for 72 hours. Methanolwas removed under reduced pressure and 5 ml of ethyl acetate were added.The aqueous phase was extracted with ethyl Aaetate (3×5 ml), the organicphase was dried under Na₂SO₄ and the solvent was removed under reducedpressure yielding the product as a yellowish oil (yield 96%).

Procedure with MCPBA.

0.5 g of (IV) wherein n is 0 were dissolved in 10 ml of THF, 0.22 g ofMCPBA (3-chloroperoxybenzoic acid, 77% assay) were added and the mixturewas stirred at RT overnight. HPLC control confirmed almost completeconversion. The solution was partitioned between 100 ml of ethyl acetateand 50 ml of an aqueous 5% solution of potassium hydrogencarbonate.Organic phase was washed with further 50 ml of basic solution and driedunder vacuum. The crude was purified on silica pad with a mixture ofethyl acetate and dichloromethane as eluent. 0.19 g of (VII) wereobtained (37% yield).

Example 20. Methanesulfonylation of (V) wherein n is 1 to Obtain(S)-3-Cyclopropylmethoxy-4-methanesulfonylaminobenzoicAcid-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester (Compound (I) wherein n is 1)

0.2 g of (V) wherein n is 1 (0.33 mmol) were dissolved in DCM (3 ml) andTEA (0.05 ml, 0.39 mmol), then methanesulfonyl chloride (0.045 g, 0.07ml) was slowly added, and solution was stirred at RT for 20 hours. Thereaction was then quenched with HCl 1N (10 ml) and the organic solventextracted and washed with a NaCl 5% aqueous solution (10 ml). Thesolvent was removed and the crude purified on column chromatography witha gradient elution (Hexane/EtOAc 85/15 to EtOAc 100%), yielding the pureproduct as a colorless oil (yield 30%).

Example 21. Preparation of 3-hydroxy-4-(difluoromethoxy)-benzoic acidmethyl ester

100 g of 3-hydroxy-4-(difluoromethoxy)-benzaldehyde (0.53 mol) weredissolved in MeOH (600 ml), solid Oxone® (325 g, 1.06 mol) was addedportion-wise in 1 hour and solution was stirred and warmed to 50-55° C.for 2 hours. The solvent was concentrated under vacuum to 200 ml andwater (1 L) was added. The resulting heterogeneous solution was stirredat 50 to 55° C., then toluene (500 ml) was added, and the biphasicmixture vigorously stirred. Aqueous phase was discharged and the organicone was washed with water (500 ml). Active charcoal (10 g) was added andthe organic solution stirred for 20 minutes. It was filtered on a celitepad, the solvent was concentrated under vacuum to 2 to 3 volumes, andthe obtained solution was warmed to 80 to 90° C. n-Heptane (400 ml) wasslowly added. The mixture was cooled to 0° C. and the suspension wasstirred at 0° C. over-night. The solid was filtered on a Buchner funneland washed with n-heptane (100 ml). The obtained white solid was driedunder vacuum at room temperature. (yield 70%).

Example 22. Preparation of3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid methyl ester

873 g of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzaldehyde (3.61mol) were dissolved in MeOH (4.4 L), then solid Oxone® (1.86 Kg, 6.06mol) was added portion-wise in 1 hour, and the solution was stirred andwarmed to 55 to 60° C. for 2 hours. The solvent was concentrated undervacuum to 1.6 L and water (7 L) was added. The resulting heterogeneoussolution was stirred at 50 to 55° C., then toluene (3 L) was added, andthe biphasic mixture vigorously stirred. Aqueous phase was dischargedand the organic one was washed with water (3 L). The solvent wasconcentrated under vacuum to 2 to 3 volumes, and the obtained solutionwarmed to 80 to 90° C. n-Heptane (5.5 L) was slowly added. The mixturewas cooled to −10° C., and the suspension was stirred at −10° C.over-night. The solid was filtered on a Buchner funnel and washed withn-heptane (1 L). The obtained yellow solid was dried under vacuum atroom temperature. (yield 52%).

Example 23. Preparation of1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-pyridin-4-yl)ethanone(Intermediate (VII), n=0)

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid methyl ester (30g, 0.11 mol) and 3,5-dichloro-4-methyl-pyridine (21.4 g, 0.13 mol) werecharged in a 1 L reactor and dissolved in THF (120 ml). The homogeneoussolution was cooled to −10° C. under stirring. A 1M solution of lithiumbis(trimethylsilyl)amide in THF (0.22 mol, 220 ml) was slowly added in30 minutes. The mixture was stirred at low temperature for 15 to 30minutes, then quenched with a 10% aqueous solution of HCl (250 ml) andwarmed to room temperature. Ethyl acetate (300 ml) was added, and thebiphasic mixture vigorously stirred for 15 to 20 minutes. Aqueous phasewas re-extracted with ethyl acetate (150 ml). The re-united organicphases were concentrated to 2 volumes. Isopropanol (240 ml) was addedand the solution was concentrated again to 2 to 3 volumes. Isopropanol(150 ml) was added and the solution was cooled to 0° C. obtaining theprecipitation of a pale-yellow solid. After 3 hours the solid wasfiltered on a Buchner funnel and washed with one volume of coldisopropanol. The obtained solid was dried under vacuum at RT. (yield90.5%).

Example 24. Preparation of3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid methyl ester

Procedure with DMF and Potassium Carbonate.

3-hydroxy-4-(difluoromethoxy)-benzoic acid methyl ester (5 g, 22.9mmol), K2CO3 (4.75 g, 34.4 mmol), NaI (0.34 g, 2.3 mmol) andbromo-methylcyclopropane (3.7 g, 27.5 mmol) were dissolved in DMF (25ml), and the heterogeneous mixture was stirred and warmed at 80° C. fortwo hours. The suspension was cooled to room temperature, and water (50ml) was added under stirring. The heterogeneous mixture was cooled to 0to 5° C. for 60 to 90 minutes, and the solid filtered on a gooch funneland washed with water (50 ml). An orange solid was obtained. It wasdried under vacuum at room temperature. (yield 95.8%).

Example 25. Preparation of3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid methyl ester

Procedure with DMA, Potassium Carbonate and MeI.

3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid (50 g, 193.6mmol), and K2CO3 (28.1 g, 203.3 mmol), were suspended in DMA (400 ml),and the suspension was warmed to 75 to 85° C. A solution of MeI (32.97gr, 232.0 mmol) in DMA (100 ml) was added through a dropping funnel in 1hour. At the end of addition the suspension was cooled to 0 to 5° C.,and water (500 ml) was added under stirring. The precipitation of awhite solid occurred. The heterogeneous cold mixture was stirred for 60to 90 minutes, and the solid filtered on a gooch funnel and washed withwater (50 ml). Product was obtained as a white solid. It was dried undervacuum at room temperature. (yield 98.1%).

Example 26. Preparation of 3-hydroxy-4-(difluoromethoxy)-benzoic acidmethyl ester

In a 50 ml flask 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzonitrile(0.5 g, 2.7 mmol), was dissolved in MeOH (3 ml), and the homogeneoussolution was stirred at room temperature. 91% Aqueous H2SO4 (1 ml) wasslowly added drop wise and the solution was warmed at 50° C. for a week.The solution was cooled to 0 to 5° C., and water (10 ml) was added, andthe obtained suspension was stirred at low temperature for 1 hour. Thesuspension was filtered on a gooch funnel. The product was obtained as awhite solid (yield 78%).

Example 27. Preparation of(R/S)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)ethanol(Intermediate (VI), n=1)

In a 100 ml round bottomed flask (VII) wherein n is 1 (0.2 g, 0.48 mmol)was added under nitrogen atmosphere, suspended in MeOH (10 ml) andcooled to 0 to 5° C. NaBH₄ (18.0 mg, 0.48 mmol) was added, and thesuspension was stirred for 1.5 hours. The reaction was quenched with H₂O(25 ml) and warmed to room temperature. The aqueous solution wasextracted twice with ethyl acetate (2×15 ml), and the re-united organicphases were dried over Na₂SO₄. The solvent was evaporated under reducedpressure obtaining a crude solid. It was dissolved in hot toluene (10ml, 85-90° C.) and crystallized by cooling the solution to 0 to 5° C.for 2 hours. The obtained solid was filtered, washed with 10 ml oftoluene and dried under vacuum in a static tray drier. 164.5 mg of whitesolid were obtained. (81.6% yield).

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

As used herein the words “a” and “an” and the like carry the meaning of“one or more.”

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

The invention claimed is:
 1. Crystal form A of3-cyclopropylmethoxy-4-methanesulfonylamino-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester, which exhibits the following XRPD peaks: 7.93; 10.32; 13.51;16.18; 20.2; and 24.87±0.2 degrees/2 theta (CuKα2).
 2. Crystal form A of3-cyclopropylmethoxy-4-methanesulfonylamino-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester according to claim 1, which exhibits the following XRPD peaks:7.93; 10.32; 12.72; 13.51; 16.18; 17.79; 18.94; 20.2; and 24.87±0.2degrees/2 theta (CuKα2).
 3. Crystal form A of3-cyclopropylmethoxy-4-methanesulfonylamino-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester according to claim 1, which exhibits the following XRPD peaks:7.48; 7.93; 8.55; 10.32; 12.72; 13.51; 16.18; 17.79; 18.94; 20.2; 23.63;24.87; and 25.82±0.2 degrees/2 theta (CuKα2).
 4. A method of treating aninflammatory or obstructive respiratory disease selected from the groupconsisting of asthma and chronic obstructive pulmonary disease (COPD),which comprises the inhalatory administration of an effective amount ofthe crystal form A of3-cyclopropylmethoxy-4-methanesulfonylamino-benzoic acid1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxy-pyridin-4-yl)-ethylester according to claim 1 to a subject in need thereof.